Omricn-(phenyl carbamyl)-nu-methyl scopolamine quaternary ammonium salts



United States Patent 'O-(PHENYL CARBAMYL)-N-METHYL SCOPOL- AMINEQUATERNARY AMMONIUM SALTS Robert B. Molfett, Kalamazoo Township,Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo,Mich., a corporation of Michigan No Drawing. Application December 5,1955,

Serial No. 550,836

3 Claims. Cl. 260-292 wherein X is a pharmacologically acceptable anion.

It is an object of the invention to provide novel and usefulO-(phenylcarbamyl) -N-methyl-scopolarnine quaternary ammonium salts.Another object of this invention is the provision of novel and usefulO(phenylcarbamyl)- N-methyl-scopolamine quaternary ammonium halides.

Other objects of this invention will be apparent to those skilled in theart to which the invention pertains.

It has now been found in accordance with this invention that the novelO-(phenylcarbamyl)-N-methyl-scopolamine quaternary ammonium saltspossess a combination of unexpected and highly useful therapeuticproperties; specifically, a combination of high antisecr'etory activitywith significant antispasmodic activity, relatively low toxicity and alack of any appreciable action on the central nervous system. This is ahighly advantageous superiority over the properties of scopolamine,esters of scopolamine and acid addition salts thereof, which adverselyaffect the central nervous system. The novel compounds of this inventionare preferably prepared from scopolamine or its acid addition salts bythe following reaction scheme:

' H O CH:CH--CH atar out n I CH2-CH CHzX l CH2-CHCH X is as definedabove.

The starting materials for the invention include the various acidaddition salts of scopolamine, such as the hydrobromide, hydrochloride,hydriodide, nitrate, sulfate,

as sodium carbonate and/or sodium hydroxide.

and the like, and the hydrates of these compounds. The acid additionsalts are first converted to the free scopolamine base by treatment withan alkaline reagent, such In the alternative, the free s'copolamine basemay be used di rectly.

The free scopolamine base is reacted with phenyl isocyanate to formO-(phenylcarbamyl)-scopolamine, which can be isolated as such, orconverted into an acid addition salt by reaction with an acid, such ashydrogen chloride in absolute ethanol. The generally crystalline acidaddition salts serve as a means for purifying the free base and arereadily reconverted to the free base by treatment with an alkalinereagent, such as sodium carbonate and/or sodium hydroxide. The freeO-(phenylcarbamyl)-scopolamine base is then converted to an N- methylquaternary ammonium salt thereof by reaction with a methyl derivative ofa pharmacologically acceptable anion, such as methyl bromide, methylchloride, methyl iodide, dimethyl sulfate, and the like. Since thepharmacological activity of th N-rnethyl quaternary ammonium salt is dueto the cation, any anion which is pharmacologically acceptable (see U.S. Patent 2,708,651) can be used.

The invention may now be more fully understood by referring to thefollowing example which is illustrative of the novel compounds of theinvention and their preparation, but .is not to be construed aslimiting.

EXAMPLE.PREPARATION OF O-(PHENYLCAR- BAMYL) l-SCOPOLAMINE METHYL BROMIDEA. O-(phenylcarbamyl) -1-sc0polamine hydrochloride To an aqueoussolution of 43.8 grams (0.1 mole) of l-scopolamine hydrobromidetrihydrate was added 120 milliliters of ten percent sodium carbonatesolution and the mixture was extracted twice with benzene. Then twentymilliliters of twenty percent sodium hydroxide solution was added to theaqueous solution and it was again twice extracted with benzene. Thebenzene solutions were combined and washed with water and then withsaturated aqueous sodium chloride. The benzene solution was then driedazeotropically by distilling a portion of the solvent under reducedpressure. A clear solution was obtained.

To this clear colorless solution (volume about 200 milliliters) ofl-scopolamine base was added 24 grams (0.2 mole) of phenyl isocyanate.The solution became warm and was cooled to room temperature and allowedto stand for nineteen hours. Then 25 milliliters of absolute ethanol wasadded and, after standing for four hours, sixteen milliliters of 6.65normal ethanolic hydrogen chloride was added. A little absolute etherwas added to initiate crystallization. After filtering, 45.5 grams (99percent) of white crystals ofO-(phenylcarbamyD-l-scopolaminehydrochlorid-e, melting point 187-192degrees centigrade with decomposition, was obtained. Onrecrystallization from about 400 milliliters of absolute ethanol, therewas obtained 37.2 grams (81 percent) of white fluffy crystals; meltingpoint l96-197.5 degrees centigrade with decomposition; [otl minu 22degrees (1.012 percent in water). A sample was recrystallized again fromabsolute ethanol to give crystals having a melting point of 196.5-198degrees centigrade with decomposition.

Analysis.-Calcd. for CZIIZ'TClNZOEI C, 62.81; H, 5.93;

- N, 6.10; CI, 7.73. Found: C, 63.00; H, 6.05; N, 6.16; Cl,

B. O-(pherzylcarbamyl)-1-sc0p0lamine methyl bromide To a cold aqueoussolution of 27.5 grams (0.06 mole) of the above once recrystallizedhydrochloride (melting point 196-1975 degrees Centigrade) was addedmilliliters of ten percent sodium carbonate solution. The mix- "ture wasextracted twice with ether; then twentymilliliters of twenty percentsodium hydroxide solution was added to the aqueous solution and it wasagain eirtracted iwicewtth sther, jne etue'r soln'tions' we're fc'onibined, 1 was er-wan water' and rhen' 'with satu'fa'ted aqueous so-'diiim *chloride, "and dried over anhydrous sodium sulfate.

- The ether was-removed by distillationa'nd theresidual methyl ethylketone. The solution was cooled, 35"gra'r'ns of coldmethyl hr'o rr'iidewas added, and the. fiaskwas stoppered'andcl'a'rnp'ed. After standingat'room temperature-for twodays," the crystalline" product, O(ph'enylcarbaniyI)'-1:s coi o1anfin methylbroniide, was collected;wjeignr 30.62 grams (98.7 percent raised on the hydro- :lil6rfde); "This'p'rodilctwasrecrystallized from 400 mil- "=liliters of 9-5 percente'tlian'ol giviing' 26.08 grams of white st'als; meningpoimj200.5-201.5degrees ceu'tigrade tilltlideorflp ds'ition; [661 5 rfiirlus'lli degrees(0.531- per- *The phenylcarbainyl) l scopolarnine methyl brodo ofthis'invention shows 'agastric'antisecretory Jac- 'vity -(ED'o) "of 0106milligram per kilogramdntra-veiinou'slyiin pyloric ligation rats. Thisvalue is the eifective dose'necessary to reduce gastric secretion byfiftypercent.

The antispasmodic activity, as determined by intravenous "injection toThiry-Vella dogs, is twenty percenfof that of atropine sulfate.

. 'Although' the example "describes the use'eithe l-scopolamine and thepreparationof'an O-(plinyl'carb-amyD-N- methyl-1-scopolamine quaternaryammonium salt, his to be understoo-d: that the corresponding d andd,l-scopolamines can likewise be employed as starting materials and whenso employed the corresponding O-(phenylcarbamyl)-N- dand d,l-scopolaminequaternary ammonium salts are obtained. I v

The-novel compounds of this invention can be com- -bined with solid orliquid pharmaceutical carriers and I formulated intoythe form oftablets, powder packets, or

capsules, or dissolved or suspended in suitable solvents,

-fororal--or==palrcntera1 administration to human beings sufiering fromgastrointestinal disorders. A suitable dosag unit is a tablet having thefollowing composition:

O-(phenylcarbamyl)-1-scopolamine methyl bromide milligrams 5 Lactose :grains- 1.3 Sucrose idoaie 0.04 St h-1. 0-0 Cale i unr stear Ido 0.02

y eu al proce ure co p t mate y m x five gram's'ofO-"(plifi ""rb? ealaanns niethylbromide with 84. grams of la ose and granulating with anaqueous solution of 2i6 'grams-of- -sheiose. After drying, the ganulesare lubricated with 4.9 grams of starch and 1.3 gramsot calcium stearate andcornpressed into tabltd oni a tabletj'nfiachine. The otherO-(pheiiylcan 'haniylf N fii'thlyl-scopolamin Iquaternary ammonium saltschiibucah b s'u titutedjfort-he O- (phenyl- Tcarb '1 -'1'-s'ce' o1aiainemethyl'bromide in this formulation.

whereinj X'; is a i-pliarmacologicallyacceptable anion.

- 2, Q-fiphenyloarbamyl)-1 -scopolamine methyl halide. -3.O-(phenylearbamyl)-l-scopolamine methyl bromide.

No references cited.

1. A COMPOUND HAVING THE FOLLOWING GENERAL FORMULA: